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WO2008044963A2 - Magnetic carrier and medical preparation for controllable delivery and release of active substances, a method of production and method of treatment using thereof - Google Patents

Magnetic carrier and medical preparation for controllable delivery and release of active substances, a method of production and method of treatment using thereof Download PDF

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Publication number
WO2008044963A2
WO2008044963A2 PCT/RU2006/000719 RU2006000719W WO2008044963A2 WO 2008044963 A2 WO2008044963 A2 WO 2008044963A2 RU 2006000719 W RU2006000719 W RU 2006000719W WO 2008044963 A2 WO2008044963 A2 WO 2008044963A2
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WIPO (PCT)
Prior art keywords
carrier
magnetic
active substance
temperature
release
Prior art date
Application number
PCT/RU2006/000719
Other languages
English (en)
French (fr)
Other versions
WO2008044963A3 (en
Inventor
Aleksandr Mettalinovich Tishin
Juri Alekseevich Rochev
Aleksandr Vladimirovich Gorelov
Original Assignee
Aleksandr Mettalinovich Tishin
Juri Alekseevich Rochev
Gorelov Aleksandr Vladimirovic
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Aleksandr Mettalinovich Tishin, Juri Alekseevich Rochev, Gorelov Aleksandr Vladimirovic filed Critical Aleksandr Mettalinovich Tishin
Priority to DE112006004066T priority Critical patent/DE112006004066B4/de
Priority to GB0906225A priority patent/GB2458229B/en
Publication of WO2008044963A2 publication Critical patent/WO2008044963A2/en
Publication of WO2008044963A3 publication Critical patent/WO2008044963A3/en
Priority to US12/421,673 priority patent/US9017713B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5094—Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B22—CASTING; POWDER METALLURGY
    • B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
    • B22F1/00—Metallic powder; Treatment of metallic powder, e.g. to facilitate working or to improve properties
    • B22F1/05—Metallic powder characterised by the size or surface area of the particles
    • B22F1/054—Nanosized particles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B22—CASTING; POWDER METALLURGY
    • B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
    • B22F1/00—Metallic powder; Treatment of metallic powder, e.g. to facilitate working or to improve properties
    • B22F1/05—Metallic powder characterised by the size or surface area of the particles
    • B22F1/054—Nanosized particles
    • B22F1/0551—Flake form nanoparticles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B22—CASTING; POWDER METALLURGY
    • B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
    • B22F1/00—Metallic powder; Treatment of metallic powder, e.g. to facilitate working or to improve properties
    • B22F1/05—Metallic powder characterised by the size or surface area of the particles
    • B22F1/054—Nanosized particles
    • B22F1/056—Submicron particles having a size above 100 nm up to 300 nm
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B22—CASTING; POWDER METALLURGY
    • B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
    • B22F1/00—Metallic powder; Treatment of metallic powder, e.g. to facilitate working or to improve properties
    • B22F1/10—Metallic powder containing lubricating or binding agents; Metallic powder containing organic material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • C—CHEMISTRY; METALLURGY
    • C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
    • C22C—ALLOYS
    • C22C1/00—Making non-ferrous alloys
    • C22C1/04—Making non-ferrous alloys by powder metallurgy
    • C22C1/047—Making non-ferrous alloys by powder metallurgy comprising intermetallic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B22—CASTING; POWDER METALLURGY
    • B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
    • B22F2998/00—Supplementary information concerning processes or compositions relating to powder metallurgy
    • C—CHEMISTRY; METALLURGY
    • C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
    • C22C—ALLOYS
    • C22C2202/00—Physical properties
    • C22C2202/02—Magnetic

Definitions

  • the invention relates to medicine, pharmacology and biotechnology, more particular, the invention relates to methods of delivery of medical or therapeutic agents or other bioactive materials to a human organism with, its controlled release into an organism.
  • instant administration of a pharmaceutical into an organism may cause the increase of its concentration, which exceeds the abilities of active sites to digest it, and may exceed capacity of the metabolic and excretory mechanism of a living organism. If the level of pharmaceutical remains increased, it may affect tissues or organs.
  • continuous controlled release of a pharmaceutical for a long period of time has essential clinical advantages.
  • administration of a pharmaceutical by intake or direct injection is connected with inconveniences of necessity of recurrent administration.
  • treatment requires recurrent pharmaceutical administration, there is . a possibility that a patient forgets or purposely does not take a pharmaceutical. If an opportunity of continuous administration of a pharmaceutical will be provided, so its controlled release during a long period of time will be carried out, necessity of recurrent administration will be eliminated.
  • syringe or needleless injectors represent containers with pharmaceutical fluid, wherefrom medical fluid through a syringe needle (or through a throttle hole of injector) under high pressure flows deep in biotissues through broken skin.
  • a method of administration (delivery) of a pharmaceutical by applying a medicated pad on a nidus with simultaneous stem of blood flow in the nidus area, and ultrasonic sound exposure for 30 minutes, with a periodic loosing of a tourniquet was disclosed in SU 556805, 05.05.77. From SU 882528, 01.04.1979, other method of administration of pharmaceuticals in an organism by a device containing carrying case, container with a medical fluid and an ultrasonic converter, is known.
  • the delivery of pharmaceutical is performed by contact action of high frequency ultrasound on a biotissue in area of pathological nidus through a wad with a pharmaceutical.
  • the high-frequency ultrasound having small amplitudes of radiator head, performs only micromassage of biotissue surface, which does not provide sufficient infiltration of a medical material through an integument, and depth of penetration does not exceed the thickness of skin epidermis.
  • the method of delivery (administration) of pharmaceuticals to a wounded surface which comprises spraying of a medical solution in the form of a medical aerosol torch, treated with ultrasound (SU 1106485, 10/22/1982), is known.
  • This method provides penetration of pharmaceuticals only in biotissue areas with a broken horny layer of skin epidermis. Delivery of pharmaceuticals deep into biotissues through intact integument is inconvenient since the horny layer of epidermis serves as a protective barrier, virtually non-permeable for liquids coming from external media.
  • the method of administration of pharmaceuticals comprises spraying of a biotissue with a medical solution in the form of a medical aerosol torch, treated with ultrasound vibration frequency of 44-66 kHz and radiator head vibration amplitude of 25-35 microns and treatment of a biotissue by low-frequency ultrasound with frequency of 26.5 kHz and vibration amplitude of 40-50 microns at exposure 5-10 s snrf 2 .
  • a local heating zone is made preliminary above the biotissue surface with temperature 40-50 0 C, which induces diaphoresis from it.
  • the biotissue is promptly cooled with a torch of an aerosol of medical material down to 20-25 0 C, and treatment with low-frequency ultrasound is performed after spraying a pharmaceutical, and simultaneously with ultrasonic an alternating magnetic field is applied with magnetic induction amplitude of 30-40 mT.
  • the said methods are designed only for delivery of a medical (therapeutic) agent to external, generally wounded surface of a biotissue, i.e. have limited applications.
  • Bioactive compound is encapsulated into a microcapsule made of biocompatible polymer or a copolymer which can pass through a gastrointestinal tract and be conserved on a mucosal surface without destruction, or being exposed to it insignificantly. This provides intake of a bioactive compound into Peyer's patches or others lymphatic tissues associated with mucous membrane and penetration into them in initial effective quantities.
  • biocompatible polymeric material is designated for a polymer which is not possessing toxicity, carcinogenic or inflammatory action in an organism.
  • microcapsules It is desirable, that an indifferent polymeric material of microcapsules was exposed to biodegradation, i.e. was decomposed during physiological processes to products which are not accumulated in tissues and excreted from an organism. Microcapsules should have such dimensions and physical and chemical properties, which would provide their effective selective intake into Peyer's patches. In the invention the problems of the directed transfer of bioactive compounds to Peyer's patches and other tissues, associated with mucous membranes and inclusions, are solved.
  • the known method concerns only the method of oral administration of an antigen to animals at which it reaches Peyer's patches and is intaken into them, stimulating, thus, immune system of mucous membrane, without loss of immunifacient activity during transport along a gastrointestinal tract.
  • the known method of oral administration of a bioactive compound to animals provides its transport and intake into Peyer's patches, for establishment of local or systemic concentration of a drug, but concerns the delivery of a certain pharmacological form of a therapeutic agent, containing a bioactive ingredient and polymeric or copolymeric inert material, preferably exposed to biodegradation, which is applicable for transport to mucous membranes by means of this method.
  • Implants have been developed for achievement of a required level of a pharmaceutical in blood during a long period of time, which provide continuous controlled release when administered to a patient.
  • Implants contain active material or a pharmaceutical in combination with a polymeric system of delivery, which controls release of the pharmaceutical.
  • the pharmaceutical is physically encapsulated in a polymeric matrix and released from a matrix by diffusion through polymer or at break of a polymeric matrix.
  • polymeric system of delivery is a biocompatible resolving polymeric matrix.
  • the polymeric matrix is not always resolving. When not resolving implants are used, surgical removal of the implant is required after release of a pharmaceutical.
  • polymeric matrices made of hydrogels, gelatin, cellulose, organopolysiloxane rubbers, polyurethanes, wax, polyvinyl alcohol), polyglycolic acid and lactic acid polymer.
  • polymeric matrix represents a copolymer of lactic acid and a glycolic acid (“PLGA", polymer of lactic glycolic acid).
  • PLGA polymer of lactic glycolic acid
  • Rate of release of a pharmaceutical depends on the set of variables, including, for example, choice of polymeric matrix, concentration of pharmaceutical in the matrix, size and form of an implant, method of implant manufacturing, surface area of implant and pore size.
  • a pharmaceutical implant which includes microparticles of one or several pharmaceuticals dispersed in a resolving polymer, which microparticles are sufficiently interrelated with each other to support the preset implant form without complete sintering of polymer, and in which implant breaks up to separate microparticles at certain time after administration.
  • Such implant is administered intramuscularly or subcutaneously.
  • a method of tumors treatment is known, based on the use of magnetic particles together with a therapeutic agent and influence of electromagnetic field.
  • the method comprises selective catheterization of hepatic artery or renal artery at kidney tumor.
  • the dispersion of barium hexaferrite or strontium in oil solution of Dioxadet is injected through a catheter to a tumor area by an external magnetic field, under control of a roentgenoscopy.
  • an arterial blood stream afterwards is reduced with a metal spiral.
  • the tumor is attacked with a microwave electromagnetic field or ultrasound for achievement of temperature in the tumor 43-43.5 0 C and the treatment continues during 5-45 minutes at this temperature. Puncture biopsy of the tumor is performed in 6-7 and in 15-20 days and, again, in 3-6 months, in presence of viable tumor cells the hyperthermia is repeated.
  • magnetoactive compounds including pharmaceuticals have wide applications. Delivery of pharmaceuticals to target organs in a human organism is one of the fundamental problems of, for example, chemotherapy.
  • One of the approaches to this problem is the use magnetosensitive carriers for pharmaceuticals, which administrated into blood vessels, transported by blood flow and are localized in a preset place by means of magnetic field.
  • Magnetosensitive and biocompatible nanospheres are known, designed for injection into vessels and localization in a certain place, which consist of a carbohydrate crystalline matrix and magnetic particles (application WO 83/01738, 1983).
  • Carbohydrate crystalline matrix is starch, glycogen, dextran or their derivatives.
  • the known carrier possesses insufficient hydrolytic and enzymatic stability.
  • Magnetic composite microspheres are also known, based on a net organosilicon polymer, which consist of a core representing magnetizable material with sizes less than 300x10 ⁇ 4 micron, evenly distributed in a net of polysilsesquioxane, containing more than 2 vinyl groups in a molecule and probably ionogenic and/or non-vinyl active group and a surface layer, representing net silicon organic polymer - application EPO 0435785, 1991.
  • the polymeric matrix of the known carrier possesses insufficient biocompatibility.
  • the carrier contains Fe 3 O 4 as magnetic particles and albumin as a polymeric covering, with mass ratio 5-350 of F ⁇ 3 ⁇ 4 to 100 of albumin.
  • the carrier provides rather fast release of a medical or biologically active material in an aqueous medium or blood, and if the microspheres are not attacked with proteolytic enzyme, the carrier conserves the integrity and activity for up to 48 hours.
  • the method has the disadvantage, as the used carrier has insufficient hydrolytic and enzymatic stability, and magnetizability.
  • the use of controlled methods of delivery of medical (therapeutic) agents by means of, for example, magnetic carriers is of high significance, as it allows delivery of a pharmaceutical to target organ under applied external magnetic field.
  • the use of magnetic pharmaceuticals generally, reduces toxicity of medical material, and also provides longer duration of action which allows to reduce doses of medical material.
  • the present work has the theoretical importance, specifically it allows to propose, what pharmaceuticals (their structural analogues) may be used for administration of magnetoactive compounds ⁇
  • the method of delivery for example, of Adriablastin with a magnetic carrier (RU 2018312, 8/30/1994) is known.
  • Technology is implemented by placing of Adriablastin on a ferromagnetic in aqueous solution with the use of freshly prepared magnetite or powder of reduced iron, as a ferromagnetic, which is preliminarily activated with 0.05 N solution of inorganic acid.
  • Magnetite and aqueous solution of a therapeutic agent are prepared separately, and then deposition of the pharmaceutical on ferromagnetic powder is , performed.
  • This step is carried out as follows: a certain volume of aqueous suspension of synthetic magnetite or activated powder of iron, containing 1 g of dry ferromagnetic, is placed into reactor vessel supplied with a stirrer. Aqueous solution of Adriablastin with concentration 1-5 * 10 ⁇ 4 M is added to the reaction mixture and stirred at 20 0 C for 0.5-4 minutes. The resulted product separated from excess of aqueous medium by decantation.
  • Magnetosensitive carrier consists of microcapsules prepared from high molecular weight organic compounds with magnetosensitive particles incorporated in them.
  • a pharmaceutical is placed on the carrier and is used for treatment of tumor diseases with utilization of directed transport of an agent to a nidus by means of external source of magnetic field (K. Widder et al., J. of Pharm. ScL 1 1976, v. 68, N 1 , pp. 79-89).
  • the method of administration of the known microcapsules assumes the use of aggressive media and/or high temperatures, which are incompatible with many pharmaceuticals.
  • the essential component of the known microcapsules high molecular weight organic compounds, represents a risk of development of allergic responses, population susceptibility to which increases during last years.
  • the method of delivery (and treatments) of a pharmaceutical to a human organism is known with the use of magnetocontrolled carrier, comprising injection through a catheter connected to vessels, feeding a tumor tissue, pharmaceuticals, sorbed on ferrocarbon particles; localization of an agent in a nidus by means of a magnet placement on body surface projected on the tumor.
  • the use of the magnet provides a gradient of magnetic density not less than 3 T rrf 1 ; and suspension of an antitumor agent administered with rate not higher than 1-2 ml min "1 is used as a local chemotherapeutic and/or radiation antitumor agent.
  • Localization of an agent in metastases takes place due to natural tropism of ferrocarbon particles to places of localization of tumor conglomerates, and after its magnetic localization in an area of tumor growth it is gradually biotransformed and the resulted complex compounds stimulate hemopoiesis and atrepsy.
  • the present method in a greater degree concerns delivery of a pharmaceutical at treatment of tumor diseases.
  • the method of delivery of pharmaceuticals controlled by magnetic field is known, in which stainless steel SUS 316L, covered with ⁇ ydrogel of magnetic gelatin is used (Li-Ying Huang et al, Abstract PSTu-L-494 of ICM 2006, Kyoto, Japan, August 20-25, 2006). Gelatin is intensively used in systems of delivery of pharmaceuticals due to its good swelling capacity and biocompatibility. Pore size of hydrogel may be controlled through a change of polymer composition, linkage conditions and concentration of magnetic precursor. Model pharmaceutical was introduced into gel film after application of magnetic field. Rate of release of the pharmaceutical noticeably decreased in comparison with the case of absence of the field.
  • heat-sensitive ferrofluids (type F 127), consisting, for example, from magnetic nanoparticles, covered with a shell from Pluronic F 127, may be used for desorption of pharmaceuticals controlled by a magnetic field (Ting
  • a pharmaceutical may be homogeneously distributed in F 127 ferrofluid below lower critical solution temperature and then at temperature above critical be encapsulated in the ferrogel. Heating of magnetic particles with alternating magnetic field may be used for formation of such gels (J. H. Park et al, J. Magn.
  • Bi 2 was increased by 20 % after application of magnetic field to the gel
  • the object of the invention is to provide a method and pharmaceutical forms for controllable delivery of a pharmaceutical or a bioactive compound. Still another object of the invention is to provide a magnetic carrier for pharmaceutical agents having enhanced effectiveness of delivery of a pharmaceutical to a designated place and enhanced effectiveness of localization in a designated place. Still another object of the invention is to provide a magnetic carrier for chemical substances and medicinal agents, having improved retention/sorbtion capacity with respect to said chemical and pharmaceutical agents, and also improved controllability of subsequent release/desorption ' of one or several chemicals/pharmaceuticals in a designated place. Still another object is widening the range of available magnetic carriers suitable for medical diagnostics, such as computer tomography.
  • poly(GMA) poly(GMA)
  • the carrier for active substances comprises: at least one material A, which is magnetically or electrically sensitive, and at least one material B capable of controlling the retention/release rate of the said active substance from the said A carrier, the said retention/release rate being temperature dependent; wherein the at least one material B is in thermal contact with material A, and wherein the material A has magnetocaloric or electrocaloric effect sufficient to vary substantially the said retention/release rate of the active substance from the carrier.
  • the invention relates to a magnetically responsive medical composition, comprising a therapeutic amount of active substance; and a carrier for active substances according to the invention.
  • the medical composition can be prepared in the form adapted for injections, such as intravenous, intramuscular, transdermal, intra-bone injections, for topical application, such as patches, for oral administration, such as tablets, capsules, drage, e.g. formulated as a unit dosage form.
  • a medical composition Especially preferable for a medical composition is the use of material A having the temperature of magnetic phase transfer within or around the interval comprising the temperature of an animal or human body.
  • material A magnetically sensitive means any material capable of spontaneous magnetic polarization in the absence of magnetic field in a certain temperature range, which is sensitive to external conditions.
  • material A electrically sensitive means any material capable of spontaneous electrical polarization in the absence of electric field in a certain temperature range, which is sensitive to external conditions.
  • material B capable of controlling a retention/release rate means that material B is selected from materials capable of influencing, in multiple ways, a retention/release rate of a substance from the carrier, whatever structure the carrier has and whatever type material B is.
  • an active substance can be adsorbed on material A, while material B can be a polymer encapsulating the material A, so that the release rate of the active substance from the carrier will be controlled by the penetration rate of the active substance through the polymer coating.
  • the release rate of the active substance from the carrier will depend on the solubility and diffusion rate of this substance in the polymer.
  • material B being a thermally sensible polymer exhibiting transition from insoluble to soluble form around LCST (low critical solution temperature), and the active substance being cells attached to the polymer surface above the LCST and "lift off" below LCST.
  • temperature-dependent means that the release rate varies with the increase/decrease of temperature significantly enough, by way of non-limiting example only, to be detected by sensors, or to change the speed of a chemical reaction, or to create a therapeutically efficient concentration in a patient organism, etc.
  • in thermal contact means that the two materials are in a contact providing a heat transfer from one material to the other, sufficient for material B to change its retention/release features when the temperature of material A changes.
  • material A is a magnetic, ferroelectric material or a combination thereof, for example material A can comprise two or more magnetic materials, or it can be a combination of magnetic and ferroelectric materials.
  • a magnetic material is selected from the group including but not limited to, rare earth metals, such as gadolinium, terbium, dysprosium, holmium, transient metals, such as iron, nickel ' , cobalt, magnesium, noble metals, such as rhodium, palladium; their oxides, compositions, combinations, solid dispersions, and alloys, such as Gd 5 Si 4 , Gd 5 Si 2 , 06 Gei,g 4 , Gd 7 Pd 3 ; MnFePo, 35 Aso, 65 and MnAs.
  • rare earth metals such as gadolinium, terbium, dysprosium, holmium, transient metals, such as iron, nickel ' , cobalt, magnesium, noble metals, such as rhodium, palladium
  • their oxides, compositions, combinations, solid dispersions, and alloys such as Gd 5 Si 4 , Gd 5 Si 2 , 06 Gei,g 4 , Gd
  • a ferroelectric material is selected form the group including compositions, complex oxides, alloys, solid dispersions and other combinations of elements of the IV group, including but not limited to lead, zirconium, titanium, tin, doped by small amounts of the elements of the III and V groups, such as scandium and niobium, including but not limited to the following materials: PbZro ,95 Tio,o 5 ⁇ 3 ,
  • material A consists of a magnetic or ferroelectric component, covered with a film of material B being a biocompatible heat-sensitive material (polymer).
  • material A is distributed in material B being a heat-sensitive medium, having properties changing at heating/cooling above/below the temperature of a human body.
  • the magnetic or ferromagnetic component is made from a material with high magnetocaloric or electrocaloric effect and with phase transition temperature close to the temperature of a human body and selected from the group, which includes rare-earth, transition and precious metals, their alloys and intermetallic compounds.
  • the magnetic or ferroelectric material can be employed in many other forms, both bulk and particulate.
  • the magnetic component or ferromagnetic material can be for example in the form having at least one dimension less than micrometer, preferably, from about micrometer to about nanometer, including nano-foil or nano-wire, for example, from gadolinium or Feo.49Rho.51 alloy.
  • the magnetic component or ferromagnetic material can be in the form of small size particles, down to nano-size, i.e. nanoparticles with sizes, for example, from several to 400 nm; preferably, from about 25 nm to about 400 nm, preferably, from 50 nm to 100 nm.
  • the carrier may be in the form of carbon tubes filled with magnetic compound or ferromagnetic material.
  • the magnetic component or ferromagnetic material may be preliminarily placed on a substrate traditionally used in manufacturing, for example, inorganic substrates, preferably, from silicon dioxide or magnesium oxide; it may be also preliminarily covered with a protective layer, for example, of graphite or silicon dioxide, or glass, which prevents its possible further oxidation.
  • a protective layer for example, of graphite or silicon dioxide, or glass, which prevents its possible further oxidation.
  • the material A and material B separately or together form a dispersion, such as suspension, aerosol, solution, colloidal solution, such as gel, including hydrogel.
  • active substance means a substance including but not limited to, a chemical agent, a pharmaceutical, a biologically active substance, biological object, a genetic construct.
  • especially preferable active substances selected from the group including but not limited to anti-inflammatory agents, antibiotics, pain killers, antiallergic, anti-histamine, anti-tumor, antivirus, anti-diabetic, anti-ulcer, anti- hyperlipidemic, anti-thrombosis agents, beta-blockers, vasodilators, bone resorbtion inhibitors and others.
  • pharmaceutical refers to a product, which includes all compounds, which cause a certain biological response.
  • pharmaceutical refers to any drug administered to mammals, including, but not limited to, humans, domestic animals, wild animals and animals raised for the use of its meat, or other products such, as agricultural animals and cattle.
  • pharmaceutical includes, but not limited to, the following classes of pharmaceuticals: therapeutic drugs, preventive drugs and diagnostic drugs.
  • Examples of pharmaceuticals which may be implanted in a polymeric matrix include but are not limited to: narcotic analgesic drugs; salts of gold; corticosteroids; hormones; antimalarial drugs; indole derivatives; pharmaceuticals for arthritis treatment; antibiotics, including Tetracyclines, Penicillin, Streptomycin and Aureomycin; antihelmintic and canine distemper drugs, applied to domestic animals and large cattle, such, as, for example, phenothiazine; drugs based on sulfur, such, as sulfioxazole; antitumor drugs; pharmaceuticals supervising addictions, such as agents controlling alcohol addiction and agents controlling tobacco addiction; antagonists of drug addiction, such, as methadone; weight-controlling drugs; thyroid gland controlling drugs; analgesics; drugs controlling fertilization or contraception hormones; amphetamines; antihypertensive drugs; antiinflammatories agents; antitussives; sedatives; neuromuscular relaxants; antiepileptic drugs; anti
  • dosage of a pharmaceutical i.e. amount of pharmaceutical in microparticles, is selected from the range about from 0.5 % (w/w) up to 95 % (w/w), preferably, from about 5 %
  • the active substance can be bonded either to material A and/or material B, or to both of material A and material B.
  • bonded herein includes but is not limited to adsorbed form, absorbed, solvated, dispersed, suspended, encapsulated form, linked by covalent bonds or Van-der-Vaals bonds, via linkers, peptide bonds, is enclosed within semipermeable membrane, or bonded by mechanical bonds or physical bonds, such as by magnetic forces or electric forces, such as dipole-dipole bonds.
  • material B is a polymeric matrix which is a resolving (biodegradable) biocompatible heat-sensitive polymer.
  • material B is any temperature- sensitive (heat-sensitive) medium or a heat-sensitive compound, in particular, heat-sensitive polymeric films and heat-sensitive hydrogels. Polymers and copolymers with lower critical solution temperature may be used as heat-sensitive polymer.
  • the following chemicals may be used as heat-sensitive monomers: N-ethyl acrylamide, N- ⁇ - propyl acrylamide, N- ⁇ -propyl methacrylamide, N-isopropyl acrylamide, N- isopropyl methacrylamide, N-cyclopropyl acrylamide, N-cyclopropyl methacrylamide, N-ethoxyethyl acrylamide, N-ethoxyethyl methacrylamide, N 1 N- disubstituted (meth)acrylamide, such as N,N-dimethyl (meth)acrylamide and copolymers based on them.
  • N-substituted acrylamides and methacrylamides, O-substituted acrylamides and methacrylamides, and also other monomers, capable to copolymerize with monomers, which form heat-sensitive polymers, may be used as comonomers for heat-sensitive copolymers.
  • the following compounds with lower critical solution temperature may be used as heat- sensitive polymers: N-vinyl caprolactam and polyoxamers based on them, such as threeblock copolymers formed from polyoxyethylene and polyoxypropylene.
  • biopolymers forming gel at increasing temperature such as methyl cellulose, may be used.
  • Heat-sensitive medium may be solutions and gels based on gelatin and collagen.
  • Heat-sensitive materials form solutions, gels, colloidal solutions, suspensions and dispersions with particles of magnetic or ferroelectric component, with the use of widely known in chemistry specific additives promoting their formation.
  • magnetic component may be a heat-sensitive ferrofluid, such as ferromagnetic fluid in the form of suspension of ferromagnetic particles in a bioactive fluid, for example, in extract of phytogenic bioactive compounds, in particular, in aloe extract; or in the form of ferrosilicon fluid.
  • ferromagnetic fluid in the form of suspension of ferromagnetic particles in a bioactive fluid, for example, in extract of phytogenic bioactive compounds, in particular, in aloe extract; or in the form of ferrosilicon fluid.
  • Bioactive compounds in the embodiment of the invention are antigens, antibodies, nucleotides, gelling agents, enzymes, bacteria, yeast, fungi, viruses, polysaccharides, lipids, proteins, hormones, carbohydrates, cellular material. These are biosensing materials for development of biosensors prepared with the use of carrier, claimed as one of the embodiments of the invention.
  • Biosensors are designed for use in composition of, in particular, sensors for bioanalytical analysis in biotechnologies, in particular, in immunoassays, widely used in clinical diagnostics for detection of diseases or physiological conditions.
  • Biosensors traditionally include substrate, layer of sensing material evenly covering said substrate, the sensing material is specific to analyte species, and when biosensor contacts with medium containing the specified analyte, these species are bonded with the said sensing material.
  • the substrate comprises a substrate from the list of materials, which includes plastics or glass, possibly, covered with metal, silicon wafers or foil, covered with the carrier, which is one of the embodiments of the invention.
  • the said sensing material is at least one of the following materials: antigens, antibodies, nucleotides, chelating agents, enzymes, bacteria, yeast, fungi, viruses, bacterial pili, components of bacterial flagella, nucleic acids, polysaccharides, lipids, proteins, carbohydrates, metals, hormones, aptamers, peptides and corresponding receptors to these materials.
  • Analyte species are, for example, at least, one of the following objects: bacterium; yeast; fungus; virus; rhematoid factor; antibodies IgG, IgM, IgA, IgD and IgE; carcinoembryonic antigen; group A streptococcus antigen; viral antigen; antigens, associated with the autoimmune disease; allergens; antitumor antigens; group B streptococcus antigens; HIV I or HIV Il antigens; viral antibodies; antigens, specific to viral respiratory infections; antibody; antigen; enzyme; hormone; polysaccharide; protein; lipid; carbohydrate; pharmaceutical; nucleic acid; Neisseria meningitides groups A, B, C, Y and subgroups 135B; Streptococcus pneumoniae; E.coli K1 ; Haemophilus influenza type A/B; antigen, obtained from microorganisms; prostate-specific antigen and CRP antigen; hapten; a pharmaceutical
  • the carrier of the invention obtained with the use of magnetic or ferromagnetic component with high magnetocaloric or electrocaloric effect in a combination with heat-sensitive material (a heat-sensitive biopolymer, heat- sensitive medium) may be also used for preparation of various implants, in particular, osteoblasts.
  • heat-sensitive material a heat-sensitive biopolymer, heat-sensitive medium
  • DMB demineralized bones
  • a human is able to induce bone growth actively, when transplanted to a human (J.N. Kearney and R. Lomez, Advances in Tissue Banking, 1997, 1 , 43-71).
  • Such materials are widely used in odontology and maxillofacial surgery as the osteoinductive ability of such allogenic bones allows to carry out transplantation of primitive cells, precursors of mesenchyma to chondroblasts or osteoblasts (CJ. Yim, Advances in Tissue Banking, 1999, 3, 87-111).
  • the method of the present invention allows to transform DMB into a compound with significantly enhanced osteoinductive activity, which accelerates formation and enriches quality of newly formed bone.
  • the use of the carrier for preparation of implants for example, osteoblasts, promotes stimulation of osteoblasts growth, speeds up delivery of these implants locally to a wound or a bone defect.
  • Such pharmaceutical implant is designed for controlled release of a pharmaceutical; after its administration in an organism with by means of applied magnetic or electrical field. It decomposes (first detached - desorbing from the substrate-carrier) to separate microparticles during certain necessary and defined period of time.
  • the invention accordingly, also provides the implant designed for controlled release of a pharmaceutical into an organism of a patient.
  • Pharmaceutical implant includes microparticles of one or several pharmaceuticals distributed in resolving (biodegraded) polymer (heat-sensitive medium), wherein the microparticles are sufficiently interrelated in order to maintain certain predefined form of the implant without complete adhesion ] of the polymer, and wherein the implant biodegrades into separate microparticles with time after administration, and wherein it covers a substrate-carrier, claimed in the invention.
  • the pharmaceutical content may be from about 0.5 to about 95 % (w/w) of microparticles. Preferably, the pharmaceutical content is from about 5 to about 75 % (w/w) of microparticles.
  • the said carrier being one of the embodiments the invention may be used for administration of a substrate (covered with a heat-sensitive polymer) in cell technologies, and provides release of the cells cultivated on it (in vitro) [for their subsequent transplantation] without use of proteolytic enzymes and dissociating agents.
  • Copolymers of N-isopropyl acrylamide (NIPAAm) and N-fe/f-butyl acrylamide (tBuAM) are mainly used as heat-sensitive polymers.
  • the release of cells is provided by decreasing of ambient temperature below the critical point defined by the phase transition temperature in aqueous polymer solutions, using a magnetic or ferromagnetic material (component) with high magnetocaloric or electrocaloric effect, as a carrier of polymeric substrate.
  • the objective of the invention is also achieved by methods of controlled delivery of a pharmaceutical or therapeutic drug or bioactive compound to an organism, including the steps of: administering into a human or animal body a medicinal composition comprising an active substance and magnetic or ferroelectric carrier, according to the invention; localizing the said active substance in a predetermined place using magnetic, electric or other suitable properties of the carrier; applying the external magnetic or electric field to effect cooling/heating of the magnetic or ferroelectric material to a temperature providing release of the active substance in a predetermined place and predetermined time.
  • a further objective of the invention is achieved by a method of treatment or prophylaxis of a disease or disorder in a patient in need of such treatment, by administering a medicinal composition according to the invention.
  • a method of treatment comprises the steps of: administering a first active substance to a patient, wherein the first active substance is bonded to material A or material B and is capable of reacting with a second active substance; wherein the first active substance is released at the predetermined time and/or pre-selected place when a second active substance is present in certain concentration in the organism or administered in certain concentration to the organism.
  • the medical composition according to the invention can, be administered in courses.
  • a method of administration of a pharmaceutical wherein the pharmaceutical consists of a medical drug or therapeutic drug, or a bioactive compound adsorbed on a magnetic material, or ferromagnetic material, covered with a film of heat-sensitive polymer, and/or distributed in other heat-sensitive medium, the method providing a controlled desorption of a pharmaceutical or therapeutic drug or bioactive compound due to phase transition from insoluble to soluble state at decreasing of medium temperature below critical point, as defined by the phase transition temperature of a polymer, and below the human body temperature.
  • a magnetic or ferromagnetic material is prepared from a material with high negative magnetocaloric or electrocaloric effect and its phase transition temperature is close to the human body temperature.
  • a magnetic or ferromagnetic material is selected from the group, which includes rare-earth, transition and precious metals, their alloys and intermetallic compounds or oxides, for example, FeRh alloys.
  • the objective is also achieved by localization of a medical or therapeutic drug or bioactive material in a target area. Decrease of temperature in a preset place, which causes desorption of a medical or therapeutic drug or bioactive material, is made by applied external magnetic or electric field and by cooling of magnetic or ferromagnetic material, which due to negative magnetocaloric and electrocaloric effect provides cooling of the heat-sensitive polymer or other heat-sensitive medium.
  • Magnetic or ferromagnetic material are particles of small size down to nanosize, furthermore, they may be prepared in the form of plates or foil, and, besides, magnetic or ferromagnetic material may be n ' anotubes filled with magnetic or ferroelectric material.
  • the magnetic or ferroelectric material may consist from nanowires made of nickel or Feo.49Rho. 51 alloy of 200 nm in diameter and 20 microns in length, they also may be prepared from magnetic nanoparticles, films or objects of other forms, other regulated or disordered bulk structure with large surface area and, hence, of high heat exchange, which prepared directly by application on a substrate.
  • Magnetic or ferroelectric material may be preliminarily coated with a thin protective layer preventing its. further oxidation.
  • the protective layer is prepared from graphite or silicon dioxide or glass.
  • the objective is also achieved by the methods of controlled delivery of a pharmaceutical or therapeutic drug or bioactive compound to an organism, including administration of pharmaceutical consisting of a medical drug or therapeutic drug, or a bioactive compound adsorbed on a magnetic material or ferromagnetic material, covered with a film of heat-sensitive polymer, and/or distributed in other heat-sensitive medium, which provides the controlled desorption of a pharmaceutical or therapeutic drug from a polymeric matrix due to phase transition from insoluble in a soluble state at increasing of medium temperature above critical point, defined by the phase transition temperature of a polymer, and above the human body temperature.
  • a magnetic or ferromagnetic material is prepared from a material with high positive magnetocaloric or electrocaloric effect and its phase transition temperature is close to the human body temperature.
  • a magnetic or ferromagnetic material is selected from the group, which includes rare-earth, transition and precious metals, their alloys and intermetallic compounds.
  • the objective is also achieved by localization of a medical drug in a target area.
  • Decrease ⁇ of temperature of a media for example, a polymer, which causes desorption of a medical or therapeutic drug or bioactive material, is made by initial heating of magnetic or ferromagnetic material by application of external magnetic or electric field to magnetic or ferroelectric material with high positive magnetocaloric or electrocaloric effect, which provides heating due to magnetocaloric or electrocaloric effect, with further natural cooling of magnetic or ferroelectric material down to temperature of adjacent tissues with final cooling of the magnetic material below the human body temperature, due to release of magnetic or electric field.
  • Magnetic material is gadolinium metal foil of 0.1 mm thjckness.
  • Ferroelectric with high electrocaloric effect (under applied external electrical field) may be prepared in the form of film based on PbZro. 95 Tio .05 O 3 (Mischenko A.S., et.al, Science, 2006, v 311 , p 1270-1271) or materials as PbSco. 5 Tao. 5 O 3 in a form of plates 20x10x0.5 mm (Y. V. Sinyavsky et. al., Ferroelectrics, 1989, v 90, pp. 213- 217).
  • an a carrier for active substances such as medical (therapeutic) agents, comprising magnetic material in the form of magnetic or ferroelectric particles provides effective transportation (delivery), localization of a medical (therapeutic) agent and its controlled release into a target area under applied external magnetic or electric field, based on the, so-called, magnetocaloric or electrocaloric effect or due to heat released, for example, at demagnetization of magnetic particles by alternating magnetic field.
  • Magnetocaloric effect or electrocaloric effect comprises heat liberation or heat absorption in magnetic or ferroelectric material under applied magnetic or electrical field. If these changes take place under adiabatic conditions they result in increasing or decreasing of sample temperature. Magnetocaloric effect was discovered by Warburg in 1881. MCE is based on the ability of any magnetic material to change its temperature and entropy under applied constant magnetic field, as it takes place at gas or steam compression or expansion or, for example, in traditional refrigerators.
  • Change of magnetic material temperature takes place as a result of redistribution of internal energy of magnetic material between the system of magnetic moments of its atoms and crystal lattice.
  • Magnetocaloric or electrocaloric effect may be used, in particular, in technology of magnetic or electrical refrigeration, for example, in air conditioning of large space rooms, in food storage equipment, and, in particular, in manufacturing of refrigeration systems, both industrial, and household.
  • Various magnetic materials are used as working bodies in magnetic refrigerators functioning on the principle of magnetocaloric cooling.
  • Magnetocaloric effect determines magnetocaloric properties of magnetic materials, and the higher the effect is, the more effective is liberation or absorption of heat in magnetic materials under magnetic field. This leads to extension of functionality of magnetic materials and increase of efficiency of medical preparations delivery to a target place and, in particular, efficiency of magnetotherapy of various diseases, for example, magnetotherapy of malignant neoplasms.
  • Examples of the materials used in the claimed , method, with high magnetocaloric effect and with phase transition temperature close to the human body temperature (from 36 0 C up to about 37 0 C) are reported in details (A.M. Tishin, Y.I. Spichkin Magnetocaloric effect and its application, Institute of Physics Publishing, Bristol and Philadelphia, 2003, pp.
  • alloys based on precious metals rhodium, palladium, platinum
  • rare-earth elements metals
  • alloys or their intermetallic compounds as, for example, iron-rhodium alloy Feo. 49 Rho.
  • Ferromagnetic material may be films based on material of the type PbZro.95Tio. 0 5O 3 or Pbo.99Nbo.o2(Zro. 75 Sn 0 .2oTio.o5)o.98O 3 (Mischenko A.S., et. al., Science, 2006, v 311 , pp. 1270-1271) or materials of the type of PbSco. 5 Tao. 5 O 3 (Y. V. Sinyavsky et. al., Ferroelectrics, 1989, v 90, pp. 213-217).
  • Both materials are used with chemical additives allowing shifting the temperature range, where high electrocaloric effect is observed, to the range of the human body temperature.
  • the electric field up to 25 V is applied during desorption process.
  • the temperature of a ferroelectric may vary up to 10-12 0 C (i.e. 0.48 k ⁇ r 1 ) A.S. Mischenko, et al., Science, 2006, v 311 , pp. 1270-1271.
  • ferromagnetic material may be 0.9(PbMnI 73 Nb 2Z3 O 3 )O-I (PbTiO 3 ).
  • V 25 V
  • the effect comprised 5 K at 60 0 C
  • Such magnetic materials or ferroelectric are used in the form of plates, foil or in the form of particles with sizes, for example, from 100 nm to 400 nm. From magnetic measurements it is known, that temperatures . of magnetic phase transitions strongly depend on concentration of alloyed metals and elements in alloys and compounds of rare-earth metals (REM). It is possible to achieve the required magnetocaloric effect and to provide required temperature, for example, of magnetic phase transition, close to the human body temperature, by variation of the content of a certain element in the alloy. Generally, for example, magnetic phase transition takes place in a wide range of magnetic fields with magnetic strength from several kE up to 60 kE (kiloerstad) and more.
  • REM rare-earth metals
  • Particles of a magnetic or ferroelectric material are prepared using various known technologies, for example, by the plasma method in inert medium (for example, under argon) from particles of one or another metal (element) with initial size, for example, 50-100 microns, or, for example, similar to the method disclosed in SU 1746162, 7/7/1992, or by deposition of nanoparticle layer on a substrate.
  • particles of carbon may be deposited on ferroelectric or magnetic particles, mentioned above, by known methods (for example, from SU 1722256, 1991). They may be used in the form of carbon nanotubes, filled or covered with ferroelectric or rhagnetic particles of materials with high magnetocaloric or electrocaloric effect. Then a heat-sensitive polymer is placed on their surface. Particle size is varied within the range from ultradispersible to nanosize.
  • heat-sensitive polymer is applied, for example, on the magnetic carrier, and medical therapeutic drugs are being adsorbed on the former.
  • Drugs are, for example, in the form of suspension and are delivered to the defined place by applying of external magnetic field with the use of magnetic particles with high magnetocaloric effect (MCE).
  • MCE magnetocaloric effect
  • the used magnetic particles should have high powder dispersity, which provides free moving of the carrier with a pharmaceutical in vessels when administrated in vitro; possess saturation of magnetization, sufficient for control of moving of the carrier with a pharmaceutical with a source of an external magnetic field of rather low intensity; provide controlled delivery of a drug to a target (preset) place. All this is provided by the use of magnetic particles with high negative or positive magnetocaloric effect.
  • the pharmaceuticals delivered to an organism of a human by the method of the invention are various medical products, drugs, enzymes, for example, such as Adriablastin, Adriamycin, riboflavin (vitamin B 2 ), novocain, Chinosolum, such antitumoral drugs as Fluorouracil, Bleomycin, Chromomycin and other medical and therapeutic drugs.
  • Concentration of the resulting pharmaceutical may be also different depending on its type and action, as the pharmaceutical is used either in the form of aqueous solutions, or in the form of solutions, suspensions in physiologically adequate carrier.
  • the heat-sensitive polymer in this case is a polymer, which desorption properties are increased at heating due to the phase transition from insoluble state to soluble state.
  • medical (or therapeutic) product may consist of two active pharmaceuticals, capable, if necessary and under certain conditions (for example, in contact and influence of an external magnetic or electrical field), to interact with each other, enhancing in such a way their medical action; and only one (first) reacting pharmaceutical is adsorbed on the carrier (described above) and its desorption is carried out, if necessary, at a moment of time and/or in a defined place, when the second reacting pharmaceutical (or bioactive material) is administered into an organism (or already is present in an organism).
  • the heat-sensitive polymer which provides controlled desorption of a medical or therapeutic drug or bioactive material in a preset place (its localization)
  • a medical or therapeutic drug or bioactive material is, for example, poly-N-isopropyl acrylamide (co)polymers, other (co)polymers of (meth)acrylamide, for example, propyl methacrylamide, polymers containing ethylene oxide groups, cellulose derivatives, for example, ethyl hydroxyethyl cellulose, cellulose acetate and others.
  • Formation of films of the heat-sensitive polymer on a magnetic or ferroelectric material (substrate, carrier) is made, for example, from alcohol solutions of polymers.
  • the heat-sensitive substrate is obtained on which surface the medical or therapeutic drug or bioactive material is then sorbed.
  • Eliminating (desorption) of a pharmaceutical is performed at decrease of temperature of a medium below the critical value defined by transition temperature of polymer in aqueous solution. Heat-sensitive polymers undergo phase transition from water insoluble (solid substrate) to soluble state at the temperature called the lower critical solution temperature (LCST).
  • LCST lower critical solution temperature
  • the content of magnetic or ferroelectric particles in the carrier may be varied from 1 up to 99 wt %; giving sorption capacity from 3.0 up to 96 %, correspondingly. Adsorptive capacity is estimated by mass of sorbed dye, methylene blue. Magnetic or electrical sensitivity of magnetic or ferroelectric particles depends on chemical composition of magnetic or ferroelectric particles.
  • the resolving (biodegradable) polymer may represent a polymer of lactic acid, glycolic acid, polyethylene glycol, poly-(or#7o-ester), polycaprolactones or their copolymers.
  • Pharmaceutical implant may additionally include one or more additives.
  • Additives may be resolving (biodegradable) polymers, mannitol, starch sugar, inosite, sorbitol, glucose, lactose, saccharose, sodium chloride, calcium chloride, amino acids, magnesium chloride, citric acid, acetic acid, hydroxyl-butanedioic acid, phosphoric acid, glucuronic acid, gluconic acid, poly-sorbitol, sodium acetate, sodium citrate, sodium phosphate, zinc stearate, aluminium stearate, magnesium stearate, sodium carbonate, sodium bicarbonate, sodium hydroxide, polyvinylpyrolidones, polyethylene glycols, carboxymethyl celluloses, methyl celluloses, starch or their mixtures.
  • Pharmaceutical implant may be of cylindrical form from about 0.5 to about 5 mm in diameter and from about 0.5 to about 10 cm in length. Preferably, its diameter is from about 1 to about 3 mm and length from about 1 to about 5 cm.
  • the cultivated cells are used, for example, fibroplasts of line NCTC clone L
  • Decrease of temperature below LCST for example, down to temperature about 32.5 0 C for the above-stated polymer, causes hydration of the polymer and release of the pharmaceutical, immunoglobulin, from the surface of substrate.
  • Heat-sensitive polymers have LCST in the physiological range. Depending on the nature of polymer, a comonomer ratio in a copolymer, it is possible to vary LCST value.
  • LCST for polymer N-isopropyl acrylamide is 32.9 0 C
  • LCST for its copolymers with N-fe/f-butyl acrylamide (tBuAM)
  • LCST varies from 25.2 0 C (15 % tBuAM) to 9.6 0 C (50 % tBuAM). Desorption is stopped with removing of external magnetic field and is proceeded at repeated application of it, and so up to the full desorption of a pharmaceutical.
  • the carrier claimed in the invention is prepared from quickly quenched alloy Fe o .5iRho.49 with high negative magnetocaloric effect.
  • the value of magnetocaloric effect in the alloy at temperature 310 K is about 4.9 KfT.
  • Particles of the alloy of 90-120 nm were covered with a film of biocompatible heat-sensitive polymer - poly-N-/so-propyl acrylamide, on which surface the pharmaceutical (immunoglobulin) was sorbed.
  • the method of delivery of this medical anesthetizing agent according to the invention is carried out as follows. Magnetocontrolled pharmaceutical is administered and magnetic field of 1 T is applied.
  • the adsorption of photoinitiator on the surface of particles of magnetic material was performed.
  • aqueous solution of photoinitiator 0.5x10 "4 M was prepared.
  • adsorption of Riboflavin on the surface of particles was achieved by their shaking with aqueous solution of Riboflavin.
  • the quantity of the adsorbed Riboflavin was deter ⁇ nined by the analysis of contacting solution by UV-vis spectroscopy, after preliminarily plotted graph of optical density at 440 nm as a function of the solution concentration. According to the analysis results, the content of photoinitiator on the particles surface corresponds to 1.5-2.0 monomolecular layers.
  • Glycerin HOCH 2 CHOHCH 2 OH, (analytical reagent) GOST 6259-52 Ethanol, CH 2 CH 3 OH, technical specifications (TU) IREA 20-66 Water distilled Interstate technical specifications (MRTU) 6-09-688-63 Riboflavin, vitamin B 2 , product of «Sigma Chemical Company», USA.
  • Particles of magnetic material with high magnetocaloric effect - iron- rhodium alloy Feo. 49 Rho. 51 are obtained, for example, using one of the known procedures by means of mechanochemistry.
  • Dextran is introduced before administration of a drug for intensifying its anesthetizing action in an organism.
  • Duration of anesthetizing action of an anesthetizing agent may be increased by using the carrier of the invention, one of the medical materials, when, for example, novocaine is absorbed on the carrier and then the material is released by the method of the invention through desorption at necessary time and in a necessary place at administration of the second medical material, for example, dextran. It is known, that novocaine does not exhibit anesthetizing action during sufficiently long period of time.
  • novocaine and dextran possess properties, allowing to use them in therapeutic practice as anesthetizing pharmaceuticals for local long-term action.
  • the novocaine content in a final product is 0.1-95.0 wt %, mainly 1-30 wt %.
  • Syntheses of novocaine and dextran were carried out by activation of hydroxyl groups of dextran by cyanogen bromide, forming cyclic iminocarbonates, which form homeopolar bonds with para-amino group of novocaine.
  • the carrier is prepared from the following material: heat- sensitive ferrofluid based on alloy Feo.51Rho.49, heat-sensitive medium - polyacrylamide. Particles of the magnetic material are covered with polyacrylamide shell (cross-linked).
  • the enhancement of medical effect may be achieved by delivery of various pharmaceuticals to an organism with the claimed method.
  • one of the pharmaceuticals adsorbed on the carrier for example, as liposomes, in the form of pharmaceutical drug, and, in particular, anti-inflammatory, antiseptic or wound-healing and antibiotics are the second medical material administered into an organism. Enhancement of the medical effect takes place due to possible interactions between them, during release (desorption) of one of them (first) and administration (at necessary time and place) of another.
  • the drug may contain lysozymes, interferons, immunoglobulins, hyaluronic acid, bioactive peptides, bifidobacteria growth factors and also antimicrobial, anti-virus or antimycotic agents.
  • bifidobacteria as a part of compositions or independently, are applied for establishment and maintenance of the normal intestinal flora, for regulation of an intestinal microflora, treatment of an intestine dysbacteriosis, dysentery, infantile colic, reactive postinfectious arthritis, atopic dermatitis, for administration of immunomodulating factor, for decrease of urea concentration in an organism, for regulation of cholesterol level in blood plasma, for biological deodorization etc.
  • binary drugs with both sorbed by the method stated above, is also possible.
  • the release of both, pharmaceutical or chemical, compounds takes place in a target place simultaneously. Then their interaction and subsequent influence on an organism or an organ result in the expected therapeutic effect at necessary moment.
  • Each of these agents or materials separately is bioinert and does not impact solely on a human organism.
  • a pharmaceutical is absorbed, which either enhances the effect of an agent or agents placed on another substrate, or mitigates its action consequences, or has, for example, another time of action, compared with the first agent.
  • the first component for destruction of a material of a capsule with the release of the second component (pharmaceutical) simultaneously or shifted in time.
  • the method may be realized, for example, as follows: quenched magnetic material Feo. 49 Rho. 51 covered with a heat-sensitive polymer together with a pharmaceutical (for example, anti-inflammatory) in the form of particles in of about 150-200 nm is administered inside of an organism through a catheter and delivery of the aforementioned particles is performed to a target organ or a tissue. Magnetic field of 2 T is applied on the area, where the particles are concentrated.
  • quenched magnetic material Feo. 49 Rho. 51 covered with a heat-sensitive polymer together with a pharmaceutical (for example, anti-inflammatory) in the form of particles in of about 150-200 nm is administered inside of an organism through a catheter and delivery of the aforementioned particles is performed to a target organ or a tissue. Magnetic field of 2 T is applied on the area, where the particles are concentrated.
  • the magnetic material is cooled by 13 0 C, which results in refrigerating of a heat-sensitive polymer, for example (co)polymer N-/so-propyl acrylamide, down to temperature below LCST, in this case down to 24 0 C, and desorption of the pharmaceutical from the surface of heat-sensitive polymer takes place.
  • a heat-sensitive polymer for example (co)polymer N-/so-propyl acrylamide
  • Example of specific realization 5 The method may be realized, for example, as follows: magnetic material
  • the heat- sensitive polymer for example, (co)polymer N-/so-propyl acrylamide
  • the magnetic field may be also formed, for example, by superconducting solenoid. Concentration of particles in a certain place of tumor raises in advance due to applied magnetic field.
  • Example of specific realization 6 Particles of a magnetic material, concentrated in a tumor, are evenly warmed up under applied magnetic field. When they warm up surrounding tissues, due to MCE heat production or due to remagnetizing of alternating magnetic fields, up to 40-42 0 C (313-315 K), cancer cells perish. Then particles cool down to initial temperature close to the human body temperature due to heat exchange with surrounding tissues; further particles of material demagnetize due to removal of permanent field (cool) and refrigerate the heat-sensitive polymer. After temperature decrease there is desorption of pharmaceutical from the surface of polymer; and after the recurrent magnetization is possible. Accordingly, they are again heated up under applied magnetic field to the necessary temperature and consequently warm up the injured tissues, i.e. the method is based on the certain thermodynamic cycle.
  • the sessions of magnetotherapy are performed by the methods of the invention, which help (together with pharmaceuticals) to kill cancer cells, keeping healthy cells safe.
  • Example 7 A procedure analogous to that described in Example 4, but administration of a pharmaceutical Adriablastin in an organism is made, when the magnetic carrier represents alloy of iron-rhodium Feo. 49 Rho. 51 , which surface is covered with copolymer NIPAAm with 35 mol % of tBuAM film, with alloy surface preliminary covered with a thin protective graphite layer (preventing oxidation); the magnetic material is prepared in the form of plates.
  • Example 8 A procedure analogous to that described in Example 4, but carbon nanotubes (20-30 nm and up to 1 mm in length), covered with magnetic iron-rhodium Feo.49Rho.51 particles of about 100 nm, are used as particles of the magnetic carrier.
  • Example 9 A procedure analogous to that described in Example 7, but gadolinium nanowires of 20 microns in length and 200 nm in diameter are used as magnetic material.
  • Example 10 A procedure analogous to that described in Example 7, but two different (or same, but modified) heat-sensitive polymers with different temperatures of phase transition differing in 5 0 C are simultaneously used.
  • Example 11 A procedure analogous to that described in Example 7, but alloys Feo.49Rho.51 and Feo.47Rho.53 are used simultaneously as magnetic carriers. Different formulation constituents are sorbed on these alloys. As value of MCE in these alloys differs in approximately 3 K under applied field of 1 T, refrigeration of the Feo. 47 Rho.53 alloy by 3.5 K will take place without phase transition in heat- sensitive polymer and desorption of the first drug. In exactly same polymer covering Feo.4 9 Rho. 51 alloy, phase transition will take place further under field of 1 T, as this alloy will cool down by 6.5 K and, hence, there will be desorption of one of components of a pharmaceutical or chemical. Under 2 T Feo. 47 Rho .53 alloy will cool by 7 K, which result in desorption of the second component.
  • Example 12 A procedure analogous to that described in Example 5, but instead of magnetic material a ferromagnetic material, a thin film based on modified material of the type of PbSco. 5 Tao. 5 O 3 is used. Modification allowed shifting the range of temperatures, where high values of electrocaloric effect are observed, to the temperature range of human body. Electric fields applied in the desorption process are up to 25 V. Temperature of the ferroelectric changes by 5-5.3 K and the film thickness is about 2 microns.
  • Example 13 (use of the carrier as a biosensor according to one of the embodiment of the invention).
  • the biosensor includes the substrate-carrier, claimed as one of the embodiments of the invention, to which bioactive materials, for example, H. Pylori antibodies or antigen-binding fragments are attached, which together with biomolecules of a heat-sensitive medium (with repelling biomolecules) form a layer of a sensing material, specific to an analyte object, such as bacteria, yeast, viruses, antibodies IgG, IgM, IgA, IgD and IgE, carcinoembryonic antigen, group A streptococcus antigens, viral antigens, antigens, associated with the autoimmune disease, allergens, antitumor antigens, group B streptococcus antigens, HIV I or HIV Il antigens, viral antibodies, antigens, specific to viral respiratory infections, antibody, antigen, enzyme, hormone, polysaccharide, protein, lipid, carbohydrate, pharmaceutical, nucleic acid, Neisseria meningitides groups A, B, C, Y and W subgroup 13
  • preparation of the biosensor for chemicals detection in fluids under analysis is based on cultures of stem cells of rat's gustatory receptors.
  • the initial cell culture enriched by olfactory receptors, is isolated preparatively from rat's tongue.
  • the lines of stem cells are isolated from initial cell culture.
  • the stem cells differentiated into cells of gustatory receptor are morphologically detected by means of optical and electron microscopies (see, for example, Mandairon N, Jourdan F, Didier A. Deprivation of sensory inputs to the olfactory bulb up-regulates cell death and proliferation in the subventricular zone of adult mice. Neuroscience. 2003; 119 (2):507-16).
  • the prepared sensory cells are placed into containers with a nutrient medium, as a part, for example, of the magnetic carrier of the invention, connected to an external device. Intrinsic electric activity of the sensory cells is registered. Calibration of the biosensor is slightly complex, as the used sensory cells contain complex assemblies of receptor molecules, each of them is responsible for reception of special group of chemicals. The descendants of various stem cells may possess various sensitivity patterns. Therefore, it is necessary to not allow uncontrollable mixture of sensory cells - descendants of various stem cells in structure of a biosensor., Calibration is carried out by method of addition of pure compounds or mixtures of chemicals, responsible for "bitter”, “acidic”, “salty”, etc.
  • Magnetic or electrical field is used as an external device.
  • the present method of the invention allows to increase efficiency of delivery of a pharmaceutical to a human organism, to increase degree of its localization in a preset place and then to perform controlled desorption of a pharmaceutical during a short period of time due to utilization of a magnetic or ferroelectric material with high positive or negative magnetocaloric or .electrocaloric effect, providing refrigerating of a heat-sensitive polymer below the LCST and desorption of a pharmaceutical or bioactive material.

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PCT/RU2006/000719 2006-10-13 2006-12-29 Magnetic carrier and medical preparation for controllable delivery and release of active substances, a method of production and method of treatment using thereof WO2008044963A2 (en)

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DE112006004066T DE112006004066B4 (de) 2006-10-13 2006-12-29 Magnetischer Träger und medizinisches Präparat zur kontrollierbaren Zuführung und Freisetzung von Wirkstoffen, Herstellungsverfahren dafür und Behandlungsverfahren unter Verwendung davon
GB0906225A GB2458229B (en) 2006-10-13 2006-12-29 Magnetic carrier and medical prepartion for controllable delivery and release of active substances
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WO2011033084A1 (de) 2009-09-21 2011-03-24 Basf Se Schaltbare ferromagnetische nanoteilchen enthaltende substrate
US20110146308A1 (en) * 2009-12-17 2011-06-23 Vincenzo Casasanta Electrocaloric cooling
GB2520960A (en) * 2013-12-04 2015-06-10 Ltd Liability Company Pharmag A magnetic field controllable implantable device and a method of controlled drug release therefrom
CN105307608A (zh) * 2013-03-15 2016-02-03 佐治亚州立大学研究基金会公司 用于将治疗剂和显像剂递送至窦和中耳的组合物和方法
US9962442B2 (en) 2011-08-10 2018-05-08 Magforce Ag Agglomerating magnetic alkoxysilane-coated nanoparticles
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CN105307608A (zh) * 2013-03-15 2016-02-03 佐治亚州立大学研究基金会公司 用于将治疗剂和显像剂递送至窦和中耳的组合物和方法
GB2520960A (en) * 2013-12-04 2015-06-10 Ltd Liability Company Pharmag A magnetic field controllable implantable device and a method of controlled drug release therefrom
GB2520960B (en) * 2013-12-04 2015-10-14 Ltd Liability Company Pharmag A magnetic field controllable implantable device and a method of controlled drug release therefrom
CN109797169A (zh) * 2019-03-06 2019-05-24 武汉轻工大学 一种基因载体及其制备方法

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RU2373957C2 (ru) 2009-11-27
US9017713B2 (en) 2015-04-28
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DE112006004066B4 (de) 2012-07-05

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